tbuckley/cabot-search huggingface dataset:
COPD detection in lung cancer screening programmes: “hitting two birds with one stone”
Authors: Juan P. de-Torres, Bartolome R. Celli
Journal: European Respiratory Journal (2022)

Lung cancer and COPD are highly prevalent smoking-related conditions associated with a high burden of morbidity and mortality worldwide [1]. Unfortunately, the diagnosis of these two diseases is strongly associated with the presence of symptoms, which usually makes the diagnosis of lung cancer occur at late, non-curative stages [2], and diagnosis of COPD occur at an older age and advanced dysfunctional condition [3]. Although tobacco smoking is the most important and most studied risk factor for both diseases, the presence of COPD has also been identified as an independent risk factor for lung cancer development [4–7]. Performing a "lung health check" could help tackle COPD and lung cancer at an earlier stage <https://bit.ly/3AAKOCu>
K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas
Authors: Selin Jessa, Abdulshakour Mohammadnia, Ashot S. Harutyunyan, Maud Hulswit, Srinidhi Varadharajan, Hussein Lakkis, Nisha Kabir, Zahedeh Bashardanesh, Steven Hébert, Damien Faury, Maria C. Vladoiu, Samantha Worme, Marie Coutelier, Brian Krug, Augusto Faria Andrade, Manav Pathania, Andrea Bajic, Alexander G. Weil, Benjamin Ellezam, Jeffrey Atkinson, Roy W. R. Dudley, Jean-Pierre Farmer, Sebastien Perreault, Benjamin A. Garcia, Valérie Larouche, Mathieu Blanchette, Livia Garzia, Aparna Bhaduri, Keith L. Ligon, Pratiti Bandopadhayay, Michael D. Taylor, Stephen C. Mack, Nada Jabado, Claudia L. Kleinman
Journal: Nature Genetics (2022)
Defining Morphologic Features of Invasion in Pulmonary Nonmucinous Adenocarcinoma With Lepidic Growth: A Proposal by the International Association for the Study of Lung Cancer Pathology Committee
Authors: Erik Thunnissen, Mary Beth Beasley, Alain Borczuk, Sanja Dacic, Keith M. Kerr, Birgit Lissenberg-Witte, Yuko Minami, Andrew G. Nicholson, Masayuki Noguchi, Lynette Sholl, Ming-Sound Tsao, John Le Quesne, Anja C. Roden, Jin-Haeng Chung, Akihiko Yoshida, Andre L. Moreira, Sylvie Lantuejoul, Giuseppe Pelosi, Claudia Poleri, David Hwang, Deepali Jain, William D. Travis, Elisabeth Brambilla, Gang Chen, Johan Botling, Lukas Bubendorf, Mari Mino-Kenudson, Noriko Motoi, Teh Ying Chou, Mauro Papotti, Yasushi Yatabe, Wendy Cooper
Journal: Journal of Thoracic Oncology (2022)

Since the eight edition of the Union for International Cancer Control and American Joint Committee on Cancer TNM classification system, the primary tumor pT stage is determined on the basis of presence and size of the invasive components. The aim of this study was to identify histologic features in tumors with lepidic growth pattern which may be used to establish criteria for distinguishing invasive from noninvasive areas.A Delphi approach was used with two rounds of blinded anonymized analysis of resected nonmucinous lung adenocarcinoma cases with presumed invasive and noninvasive components, followed by one round of reviewer de-anonymized and unblinded review of cases with known outcomes. A digital pathology platform was used for measuring total tumor size and invasive tumor size.The mean coefficient of variation for measuring total tumor size and tumor invasive size was 6.9% (range: 1.7%-22.3%) and 54% (range: 14.7%-155%), respectively, with substantial variations in interpretation of the size and location of invasion among pathologists. Following the presentation of the results and further discussion among members at large of the International Association for the Study of Lung Cancer Pathology Committee, extensive epithelial proliferation (EEP) in areas of collapsed lepidic growth pattern is recognized as a feature likely to be associated with invasive growth. The EEP is characterized by multilayered luminal epithelial cell growth, usually with high-grade cytologic features in several alveolar spaces.Collapsed alveoli and transition zones with EEP were identified by the Delphi process as morphologic features that were a source of interobserver variability. Definition criteria for collapse and EEP are proposed to improve reproducibility of invasion measurement.
ABC transporters: human disease and pharmacotherapeutic potential
Authors: Jonathan M. Moore, Eric L. Bell, Robert O. Hughes, Alastair S. Garfield
Journal: Trends in Molecular Medicine (2022)

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are a 48-member superfamily of membrane proteins that actively transport a variety of biological substrates across lipid membranes. Their functional diversity defines an expansive involvement in myriad aspects of human biology. At least 21 ABC transporters underlie rare monogenic disorders, with even more implicated in the predisposition to and symptomology of common and complex diseases. Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery, as exemplified by the transformative CFTR (ABCC7) modulator therapies for cystic fibrosis. This review will explore the growing relevance of ABC transporters to human disease and their potential as small-molecule drug targets.
Reliability and validity of the Chester step test in patients with interstitial lung disease
Authors: A. Alves, A. Oliveira, P.G. Ferreira, V. Martins, A. Marques
Journal: Pulmonology (2022)

The Chester Step Test (CST) is a simple and inexpensive field test, which requires minimal physical space to assess exercise capacity. Such characteristics make the CST suitable to be used in different settings, however, its measurement properties in patients with interstitial lung diseases (ILD) are unknown.
Monitoring the in vivo siRNA release from lipid nanoparticles based on the fluorescence resonance energy transfer principle
Authors: Lei Sun, Jinfang Zhang, Jing-e Zhou, Jing Wang, Zhehao Wang, Shenggen Luo, Yeying Wang, Shulei Zhu, Fan Yang, Jie Tang, Wei Lu, Yiting Wang, Lei Yu, Zhiqiang Yan
Journal: Asian Journal of Pharmaceutical Sciences (2022)

The siRNA-loaded lipid nanoparticles have attracted much attention due to its significant gene silencing effect and successful marketization. However, the in vivo distribution and release of siRNA still cannot be effectively monitored. In this study, based on the fluorescence resonance energy transfer (FRET) principle, a fluorescence dye Cy5-modified survivin siRNA was conjugated to nanogolds (Au-DR-siRNA), which were then wrapped with lipid nanoparticles (LNPs) for monitoring the release behaviour of siRNA in vivo. The results showed that once Au-DR-siRNA was released from the LNPs and cleaved by the Dicer enzyme to produce free siRNA in cells, the fluorescence of Cy5 would change from quenched state to activated state, showing the location and time of siRNA release. Besides, the LNPs showed a significant antitumor effect by silencing the survivin gene and a CT imaging function superior to iohexol by nanogolds. Therefore, this work provided not only an effective method for monitoring the pharmacokinetic behaviour of LNP-based siRNA, but also a siRNA delivery system for treating and diagnosing tumors.
Re: Laura S. Mertens, Richard P. Meijer, J. Alfred Witjes. Positron Emission Tomography/Computed Tomography for Staging of Bladder Cancer: A Continuing Clinical Controversy. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2022.09.017
Authors: Fredrik Liedberg, Elin Trägårdh
Journal: European Urology (2022)
Corrigendum to “Young Age on Starting Prostate-specific Antigen Testing Is Associated with a Greater Reduction in Prostate Cancer Mortality: 24-Year Follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial” [Eur Urol (2022)]
Authors: Sigrid V. Carlsson, Rebecka Arnsrud Godtman, Carl-Gustav Pihl, Andrew Vickers, Hans Lilja, Jonas Hugosson, Marianne Månsson
Journal: European Urology (2022)
Abstract PR011: Histone demethylase KDM5D drives sex-specific differences in colorectal cancer
Authors: Jiexi Li, Zhengdao Lan, Wenting Liao, James W. Horner, Jielin Liu, Shan Jiang, Hong S. Shim, Max Slotnik, Kyle A. LaBella, Wen-Hao Hsu, Denise J. Spring, Y. Alan Wang, Ronald A. DePinho
Journal: Cancer Research (2022)

Abstract Gender exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible oncogenic Kras transgene (KRAS*) and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with KRAS* CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of epithelial cell tight junction and MHC class I complex components. Deletion of KDM5D in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive KDM5D expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, thus providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC. Citation Format: Jiexi Li, Zhengdao Lan, Wenting Liao, James W. Horner, Jielin Liu, Shan Jiang, Hong S. Shim, Max Slotnik, Kyle A. LaBella, Wen-Hao Hsu, Denise J. Spring, Y. Alan Wang, Ronald A. DePinho. Histone demethylase KDM5D drives sex-specific differences in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR011.
Abstract B019: APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer
Authors: Christopher Lengner
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally, with the majority of cases initiated by inactivation of the APC tumor suppressor. This results in the constitutive transcriptional activation of the canonical WNT signal transduction pathway effector b-Catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM. Here, we show that NOTUM retains cell-autonomous tumor suppressive activity in APC-null adenomatous lesions despite constitutive b-Catenin activation. Strikingly, we find that NOTUM becomes an obligate oncogene upon subsequent P53 inactivation during the adenoma-adenocarcinoma transition, and that these phenotypes are WNT-independent, resulting from differential activity of NOTUM upon its enzymatic targets Glypican 1 and 4 in early vs. late-stage disease, respectively. Ultimately, preclinical mouse models of CRC and human tumoroid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonization of distal organs. The finding that a single agent targeting an extracellular enzyme is effective in treating highly aggressive tumors make NOTUM a novel therapeutic vulnerability in advanced colorectal adenocarcinomas. Citation Format: Christopher Lengner. APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B019.
Abstract IA025: Stem and metaplastic cell states and their influences on the tumor immune microenvironment in colonic pre-cancerous lesions
Authors: Ken S. Lau
Journal: Cancer Research (2022)

Abstract The immune microenvironment is critical to colorectal cancer (CRC) pathogenesis, regarding both prognosis and therapeutic responses. While much work has been done to characterize tumor microenvironments, less is known about those environments are established following transformation of epithelial cells. We hypothesize that mapping routes towards CRCs, from normal human colonic tissues and precursor polyps, will uncover additional mechanisms that define the CRC cellular landscape and identify targets with diagnostic or therapeutic utility. Here, we present a comparative atlas of the two most common colorectal precursor lesions, conventional adenomas and serrated polyps, and their resulting CRC counterparts using single-cell transcriptomics and multiplex imaging across two cohorts of human participants. Integrative analysis reveals adenomas arise from dysregulated WNT-driven expansion of stem cells, while serrated polyps are depleted of stem cell populations and are derived from differentiated cells transitioning through a pyloric metaplasia program. Mucosal damage associated with metaplasia is coupled to a cytotoxic immune microenvironment that precedes hypermutation. Mouse and organoid experiments validate the importance of the differentiation states of colonic tumor cells in driving cytotoxic immunity partly through increased expression of antigen-presentation machinery. These data provide constitute a rich resource into malignant progression of colorectal polyps and their microenvironments, serving as a framework for precision surveillance and prevention of CRC. Citation Format: Ken S. Lau. Stem and metaplastic cell states and their influences on the tumor immune microenvironment in colonic pre-cancerous lesions [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA025.
Abstract IA019: Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights
Authors: Shuji Ogino
Journal: Cancer Research (2022)

Abstract This lecture discusses the integration of tumor microbiology and immunology into evolving/expanding molecular pathological epidemiology (MPE) research framework (Ogino et al. Gut 2011; Ogino et al. Annu Rev Pathol 2019; Inamura et al. Gut 2022; etc.), which will open new opportunities. Neoplasms represent heterogeneous pathological processes due to interactive influences of the exposome (including the microbiome), the immune system, and neoplastic cells. Hence cancers should be regarded as not only microenvironmental diseases but also environmental and systemic diseases (Inamura et al. Gut 2022). To address this complexity, we investigate influences of exposures on microbial-tumor-immune interactions in tumor microenvironment. Colorectal cancer (CRC) provides an ideal model, as the colorectum is the most microbial rich organ and there are many established or putative risk factors for CRC. In our proof-of-principle studies that used the Nurses’ Health Study and Health Professionals Follow-up Study along with tumor tissue biobanks having 1700 CRC cases, we can provide evidence for influences of prudent diets (Mehta et al. JAMA Oncol 2017), inflammatory diets (Liu et al. Clin Gastroenterol Hepatol 2018), and western diets (Arima et al. Gastroenterology 2022) on developments of cancer subtypes with intratumor bacteria such as Fusobacterium nucleatum and pks+ Escherichia coli. We have also gain insights into interactions between microbes and immune cells. We have discovered an inverse relationship between F. nucleatum and T cell infiltrates (Mima et al. JAMA Oncol 2015), especially CD3+CD4+CD45RO+ memory helper T cells (Borowsky et al. Clin Cancer Res 2021). In situ spatial single cell analyses using multispectral fluorescence imaging and machine learning can shed light on the roles of microbes as well as various immune cell infiltrates in CRC (Vayrynen et al. Cancer Immunol Res 2021; Vayrynen et al. J. ImmunoTher Cancer 2021; Vayrynen et al. Cancer Immunol Res 2022; Akimoto et al. Front Immunol 2022). The integrative MPE approach is also expected to advance research on early-onset cancers (Akimoto et al. Nat Rev Clin Oncol 2021; Ugai et al. Nat Rev Clin Oncol, in press). Our new research paradigm to integrate microbial and immune assays on archival tumor tissue in large-scale population studies can provide not only etiological insights but also possible paths for precision medicine and prevention. Citation Format: Shuji Ogino. Molecular pathological epidemiology of tumor microbiota and immunity can give etiologic insights [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA019.
Abstract IA017: Microbiota drivers of colorectal cancer and their translation to prevention
Authors: Cynthia L. Sears
Journal: Cancer Research (2022)

Abstract Abundant data support that the microbiota, both communities and individual pathogenic bacteria, promote the development of colorectal cancer (CRC). More limited data support that CRC is initiated by specific bacteria or communities. This talk will focus on bacterial contributors to CRC pathogenesis, potential mechanisms, gaps in knowledge and potential approaches to enabling use of the colon microbiota and its members to advance CRC prevention. Improved approaches to prevention are particularly key to identify those at risk for early onset CRC that represents a global change in CRC epidemiology. Citation Format: Cynthia L. Sears. Microbiota drivers of colorectal cancer and their translation to prevention [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA017.
Abstract B007: LIN28B promotes collective cell invasion and colorectal cancer metastasis via a novel CLDN1 and NOTCH3 axis
Authors: Alice E. Shin, Kensuke Sugiura, Yasunori Masuike, Kensuke Suzuki, Christopher J. Lengner, Anil K. Rustgi
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death worldwide. The 5-year survival rate is 90% in patients with localized tumors, but the survival rate drastically decreases to 14% in patients with distant metastasis. Therefore, it is imperative to elucidate the molecular mechanisms underlying CRC metastasis. The RNA-binding protein LIN28B is overexpressed in over 30% of patients with CRC and is associated with poor prognosis. Indeed, our previous work revealed that LIN28B promotes liver metastasis in a subcutaneous xenograft model of CRC as well as a portal vein injection model. In the present study, we investigated the mechanism by which LIN28B promotes colorectal tumor progression and metastasis. To assess biological changes induced by LIN28B, we established CRC cells (DLD-1 and LoVo) with high expression of LIN28B (LIN28Bhigh). LIN28B overexpression upregulated Claudin-1 (CLDN1), a protein that functions as a major constituent of the tight junction complexes. RNA immunoprecipitation revealed that LIN28B directly binds to and stabilizes CLDN1 at a post-transcriptional level. Knockdown of CLDN1 expression in LIN28Bhigh cells suppresses cell aggregation, wound healing rate, and collective invasion. Using a mouse model of metastatic CRC, we reveal that knockdown of CLDN1 inhibits liver metastasis of LIN28Bhigh CRC cells. RNA-sequencing of metastatic liver tumors from LIN28Bhigh cells showed that NOTCH3 works downstream of the LIN28B-CLDN1 axis to induce cell aggregation, collective invasion, and metastatic liver tumor formation. Inhibition of Notch signaling by DAPT, an inhibitor of the γ-secretase complex, significantly reduced metastatic liver tumors in vivo. Taken together, our results indicate that LIN28B promotes cell aggregation, invasion, and liver metastasis in CRC through post-transcriptional induction of CLDN1 and upregulation of NOTCH3. Development of new therapies that target LIN28B-CLDN1-NOTCH3 axis may provide an effective strategy for stage 4 CRC. This work was supported by 9R01CA277795-22. Citation Format: Alice E. Shin, Kensuke Sugiura, Yasunori Masuike, Kensuke Suzuki, Christopher J. Lengner, Anil K. Rustgi. LIN28B promotes collective cell invasion and colorectal cancer metastasis via a novel CLDN1 and NOTCH3 axis [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B007.
Abstract IA020: The gut microbiome in colorectal cancer
Authors: Chloe E. Atreya
Journal: Cancer Research (2022)

Abstract The gut microbiome plays important roles in colorectal cancer (CRC) initiation, treatment, and survivorship. This talk will highlight preliminary results from two pilot studies: Gut microbiome &amp; Oral fluoropyrimidines (GO) and Lifestyle and Outcome in Gastrointestinal Cancer (LOGIC). GO investigated the impact of oral fluoropyrimidines (e.g., capecitabine) on gut microbes via longitudinal stool sampling. Despite marked inter- and intra-individual differences in diversity and community structure, we detected multiple consistent taxonomic differences. LOGIC asked: how do diet and lifestyle, measured by the American Cancer Society (ACS) score, correlate with gut microbiota characteristics in CRC survivors? We found that components of the ACS score related to fruit and vegetable consumption, but not the overall ACS score, significantly associated with variations in microbial community structures, diversity, and differences in abundance of microorganisms at various taxonomic levels. Practical considerations influencing the design of follow-up studies in progress will be discussed. Citation Format: Chloe E. Atreya. The gut microbiome in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA020.